Diabetes is a disorder of sugar metabolism due to deficiency in the production of insulin by the pancreas or ineffectiveness of the insulin produced. The disease causes increased levels of glucose in the blood and results in damages to many of the body's tissues or organs, such as the blood vessels and the nerves.
There are two forms of diabetes, type I diabetes and type II diabetes. Type I diabetes, also called insulin-dependent diabetes mellitus (IDDM), normally develops in children and the patients must administer insulin by injection for their entire life time. Type II diabetes, also called non-insulin-dependent diabetes mellitus (NIDDM), is highly associated with high fat diet and obesity. There are many medications to treat Type 2 diabetes, including drugs that reduce glucose through urination such as INVOKANA® (canagliflozin), a sodium-glucose co-transporter 2 (SGLT2) inhibitor releasing excess glucose in the body through urination; drugs that increase insulin sensitivity such as GLUCOPHAGE® (metformin), ACTOS™ (pioglitazone), and AVANDIA® (rosiglitazone); drugs that stimulate insulin production by the pancreas such as Sulfonylureas and non-sulfonylurea secretagogues; and drugs that slow digestion of carbohydrates such as alpha-glucosidase inhibitors and amylin analogues and dipeptidyl peptidase-4 inhibitors (DPP-4). BYETTA® (Exenatide) is a newly developed injectable drug which is a glucagon-like-peptide-1 (GLP-1) analog and lowers blood sugar by increasing the release of insulin from the pancreas. However, there still have some limitations and possible side effects for these anti-diabetic drugs, such as hypoglycermia, weight gain, cardiovascular problems, nausea and flatulence. As a result, there remains a need for alternative drugs for treatment of diabetes. So far no report discloses use of a TLR-4 antagonist for treatment of diabetes.
TLR-4 is a member of the Toll-like receptor (TLR) family. It is a cell surface, transmembrane receptor which primarily recognizes bacterial lipopolysaccharides and upon activation plays an important role in the induction of inflammatory pathways.
There is increasing evidence that the production and secretion of pro-inflammatory factors in vascular cells play an important role in atherosclerosis. Intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and E-selectin are major biomarkers and endothelial cell (EC) adhesion molecules that regulates the binding and extravasation of leukocytes from the bloodstream to sites of inflammation (Sato J et al., PLoS One 9:e107236). When ECs are activated in response to cytokines, the expression of cell adhesion molecules on their surface is increased markedly. The appearance of soluble cell adhesion molecules in the circulation is thought to be the consequence of their release from the surface of activated ECs because of increased expression (Tesfamariam B et al., Vascul Pharmacol 46:229-237). Several reports have demonstrated the importance of soluble forms of adhesion molecules in the microvascular and macrovascular complications that can arise in patients with type 2 diabetes (Herder C et al., PLoS One 6:e19852; Kalofoutis C et al., Exp Clin Cardiol 12:17-28). Some reports have shown that diabetes mellitus (DM) is associated with atherosclerotic and inflammatory disease (Kim J A et al., Circulation 113:1888-1904; Orasanu G et. al., J Am Coll Cardiol 53:S35-42). Among the cardiovascular risk factors documented in diabetes, hyperglycemia appears to be an independent risk factor for diabetic vascular complications (Monnier L et. al., JAMA 295:1681-1687; Wright R J et al., Diabetes Metab Res Rev 24:353-363).
Some reports have shown that loss of TLR4 function partially protects against peripheral and cardiac glucose metabolic derangements during a long-term high-fat diet and a TLR4 antagonist protects against aldosterone-induced cardiac and renal Injury (Jackson E E et al., PLoS One 10:e0142077; Zhang Y et al., PLoS One 10:e0142456). Some reports also have shown that TLR-4 is associated with colorectal cancer progression and metastasis, gastric cancer progression, periodontitis and urinary tract infection (Chen T C et al., Cell Microbiol 13:1703-1713; Chrzeszczyk D et al., Adv Clin Exp Med 24:1059-1070). Lu et al. disclose that Rs-LPS used as a TLR4 antagonist has no effect on glucose and lipid changes induced by high-fat diet, suggesting that Rs-LPS inhibits atherosclerosis in diabetic LDLR−/− mice through mechanisms independent of metabolic control (Lu Z et al., Immunobiology 220 (11): 1246-1254).
Pneumolysin, an intracellular thiol-activated toxin with cytolytic and complement activating properties, is one of the major virulence factor containing in all Streptococcus. pneumoniae (Rabes A et al., Curr Top Microbiol Immunol 397:215-227). S. pneumonia infections are responsible for the induction of inflammation caused by pneumolysin, which damages the blood vessels in the lungs and causes bleeding into the air spaces. Also, recent study shows that pneumolysin is possibly a chemo-attractant of neutrophils transendothelial migration in pneumonia model (Moreland J G et al., Am J Physiol Lung Cell Mol Physiol 290:L833-840).